Introduction

The leukaemias can be classified as acute or chronic, and sub-classified as myeloid or lymphoid. Thus, there are four classifications:

ALL – acute lymphoblastic leukaemia–this is mainly a disease of childhood. It is the most common malignancy of childhood.

AML – acute myeloid leukaemia

CLL –chronic lymphocytic leukaemia – this is mainly a disease of the elderly

CML –chronic myeloid leukaemia

Leukaemia (mostly ALL) is the most common malignancy of childhood – accounting for about 30% of childhood malignancy. The other main three forms of leukaemia – AML, CLL and CML can occur in childhood, but are primarily diseases of adulthood, and most commonly present in patients over 55.

The leukaemias, along with lymphomas and myelomas are a related spectrum of haematological malignancies. They are generally uncommon, but not rare, with the lymphomas being the 7th most common cancer in the United Kingdom.

Although the precise aetiology of all these diseases is unknown, it is thought to be multifactorial.

The way in which these diseases are classified is becoming increasingly complicated and diverse. For example, In childhood leukaemia (80% ALL, 15% AML, 5% other), many varied different chromosomal and genetic factors have been implicated.

Treatment often involves immuno- and myelosuppression – which in itself can be life-threatening, but can sometimes be curative.

It is important upon disease onset to discuss with the patient whether a curative or palliative approach is more appropriate and the rationale for this. Also, the possibility of treatment failure needs to be addressed at the outset, and not at any later point.

Epidemiology

Leukaemia is relatively rare, having an incidence of about 10 per 100 000

Just over half are acute in presentation

Males are more commonly affected than females; the ratios vary for different types of leukaemia, but are roughly 3:2 to 2:1

Chronic leukaemias generally occur in middle and old age

Acute leukaemias can occur at any age; acute lymphoblastic leukaemia is more common in childhood, whilst acute myeloid leukaemia most commonly occurs over the age of 50

Aetiology

Basically this is unknown, but several factors are thought to be involved:

Radiation – this can induce damage to hemopoietic precursors, and ALL, AML and CML are all seen in increased incidence in survivors of Hiroshima and Nagasaki, as well as in those treated with irradiation therapy. X-rays of the foetus also increase the risk later in life.

Genetic abnormalities

The genetic abnormality can be of diagnostic and prognostic significance. The abnormalities alter the cell cycle resulting in decreased apoptosis.

The Philadelphia (Ph) chromosome is the most common genetic abnormality. It is associated with 97% of cases of CML. This defect is also found in ALL, with incidence increasing with age.

Ph is an abnormal chromosome 22. There is a reciprocal translocation, i.e. a “swap” between chromosomes 22 and 9. The long arm of chromosome 22 becomes shorter.

The new “fusion gene” is called BCR-ABL. This gene produces an abnormal protein that allows for excess phosphorylation which ultimately alters cell growth and apoptosis mechanisms.

ABL is a proto-oncogene found on chromosome 9. BCR is a normal gene coding for a protein found on chromosome 22. After translocation, ABL gets moved next to BCR, culminating in BCR-ABL

Cell surface markers

These can be used to classify acute leukaemias. Different surface antigens are displayed at different stages of myeloid cell development. Thus by determining which surface antigens are expressed by a specific type of leukaemia, one can roughly establish at which point in myeloid cell development the defect lies, and classify the leukaemia.

Basic pathology

There is proliferation of primitive stem cells, and leading to an accumulation of blasts, predominantly in the bone marrow, which causes bone marrow failure. In chronic leukaemia, the malignant clones are themselves able to differentiate, and the accumulated cell population in the bone marrow is made up of a more mature variety of cells, and not just blast cells.

Diagnosis

There is usually a raised white cell count, and this is where the abnormality is often first noted. The actual diagnosis is made from examination of bone marrow where this examination includes:

Remember: The point of this analysis is not just to identify which cell type is present; bone marrow examination is also essential for determining prognosis and treatment.

Myelodysplastic syndromes (MDS)

MDS are generally considered precursors to leukaemia. 30% of all individuals suffering with MDS will go on to develop acute myoblastic leukaemia (AML).

This term encompasses conditions that are due to a defect in myeloid stem cells. These syndromes are acquired, and generally occur in the elderly.

There is usually an associated pancytopaenia.

The natural history of MDS is variable, but there is a high morbidity and mortality.

Clinical features

Mainly occurs in the elderly

Presents with symptoms of anaemia, infection, and/or bleeding, due to pancytopaenia

Blood films will show:

thrombocytopaenia

neutropaenia

anaemia

monocytosis – however, the level does not rise higher than 1 x 1019/L.

Bone marrow often decreases in cellularity despite pancytopaenia

The number of blast cells in the bone marrow is increased

Management

Patients with <5% blast cells in the bone marrow are managed conservatively:

Red cell infusions

Platelet infusions

Antibiotics for infection

Hemopoietic growth factors, e.g. EPO and C-GSF are useful in some patients

Patients with >5% blast cells in the bone marrow have a worse prognosis. Their management may include:

Supportive care only – usually for the very old, and those with other, unrelated medical problems

Gentle chemotherapy – this is usually a low dose of a single agent, e.g. azacytidine, helpful if there is a particularly high WBC count

Intensive chemotherapy – this will probably involve similar regimens to those used in AML. The remission rate, however, is poor, and because of the defects in stem cells pancytopaenia can be worsened, because the stem cells can’t generate new cells quickly.

Bone marrow transplant – this is curative in some patients – however, there must be an HLA match, i.e.usually a sibling, or more unlikely, a matching donor. Patients must also be under the age of 50 to be considered for this treatment.

Acute Leukaemias

Acute lymphoblastic leukaemia (ALL) is the most common type in children, primarily affecting 2 to 8 year-olds. There is equal risk between males and females, while all other leukaemias occur more frequently among males

Accounts for 80% of all childhood leukaemias

Peak age of incidence in children is age 2-3

Acute myeloid leukaemia (AML) in adults is about 4xs more common than ALL in adults. It may occur in children too, but this is rare. Approximately 2/3s of AML patients are over 60

Accounts for about 15% of childhood leukaemias

Peak age of incidence in children is <2

Generally, the prognosis for acute leukaemias is poor. There is a failure of cell maturation, translating into a build-up of immature cells in the bone marrow. These cells are pretty much useless, occupying marrow space and denying normal cells vital resources. Eventually these cells will accumulate to a point such that they will spill out into the blood.

Aetiology

More common in caucasians

Boys at slightly higher risk

Wide range of genetic mutations have been implicated

Risk is greatly increased when another genetic disorder s present (e.g. 20x greater in Down Syndrome)

Petechiae – these are little purple spots, about 1-2mm diameter caused by rupture of a small blood vessel

Lymphadenopathy – in lymphoblastic leukaemia

Hepatosplenomegaly – in lymphoblastic leukaemia

Violaceous skin lesions – AML

Testicular enlargement – ALL

Cranial nerve palsies – ALL, but quite rare

Investigations

Blood count – ↓Hb; ↑WCC; ↓platelets

Blood film – blast cells nearly always seen; auer rods might also be seen, which are pathognomonic for AML; in ALL there are more likely to be large blast cells, i.e. these cells are smaller and more mature in chronic leukaemias

This image shows a blast cell. Its granular appearance suggests that it is of myeloid origin.

Note its large size and primitive nucleus.

Differentiating between ALL and AML

ALL

AML

Presence of auer rods in blood

None

Always present

Presence of lymphoblasts in blood

Always present

May or may not be present

Bone and joint pain

More common

Less common

Hepatosplenomegaly

More common

Less common

Organ infiltration

More common

Quite unusual

Management

The acute leukaemias are fatal within months if not treated.

Generally, ALL in children has the highest chance of being curable of all the acute leukaemias.

Curative therapy has a varible success rate depending in the type of leukaemia and prognositc factors.

Curative therapy may fail either because the patient cannot tolerate it, or because it fails to destroy the causatory cells.

Curative treatment carries considerable risk. The acute leukaemias can be classified as high risk or low risk. Low-risk leukaemias include ALL in childhood. AML in an adult with adverse cytogenic features may be considered a high-risk leukaemia. Generally, the higher the risk, the greater the morbidity/mortality induced by treatment.

Factors that suggest high-risk treatment include:

antigens expressed on the cell surface, which are suggestive of the mutation involved

age greater than 60

leukaemia following on from MDS

relapsed disease

extramedually disease

secondary leukaemia

In cases deemed unsuitable for curative treatment (or in cases where the patient decides against curative treatment), then palliative treatment can be undertaken. This can extended life expectacny, typically to 12-18 months.

Curative treatment

The decision to treat should not be taken lightly. Treatment will greatly impact on the patient’s life for 6 months to a year, requiring admission to a specialist centre, after which he/she “may never feel the same again”.

Curative care carries with it significant risks and should only be attempted where there is chance of success. ALL in children has the highest success rate of curative treatment. In some cases, however, the failure rate is very high. If the possibility of cure ceases to exist during therapy, management strategies should be switched to palliative treatment.

The aim of curative treatment is to destroy clonal cells without destroying normal stem cells, so that the latter will be able to repopulate after clonal cells destruction. There are three phases to treatment:

Remission induction through whichthe majority of the tumour will be destroyed by ‘induction chemotherapy’. This will result in massive bone marrow hypoplasia. The patient will need a great deal of supportive care during this phase, and is likely to be in intensive care. The treatment greatly reduces the normal white cell count and therefore the patient is at very high risk of life-threatening infection. Isolation precautions will be exercised whilst they are in hospital with the likelihood of confinement to a single side room

Remission consolidation is carried out once normal haematopoiesis is achieved; the remaining tumour will be attacked utilising further therapy. This consists of further courses of chemotherapy, resulting in more bone marrow hypoplasia. Where prognosis is deemed to be poor this may involve bone marrow transplant. If phase one was successful and successive treatment is not offered, there will almost certainly be relapse of the disease. The aim of this phase is to achieve complete remission (CR)*

Complete remission is rare. It may initially appear to be the case, but to be certain that it is achieved morphological testing of leukaemic cells is carried out. The presence of leukaemic cells at this stage is a bad prognostic sign.

Maintaining remission. If both of the above treatment phases have been successful, then further therapy, given on an outpatient basis, may be required for up to 3 years. After the 3-year period no further treatment will be offered but the patient will be closely observed. This is only the case in ALL,and is not thought to be of benefit in patients with AML.

*Complete remission – there is a bit of confusion over what this actually means. It may be defined as no signs of disease on microscopy. However,even when this is deemed the case, there may still be some abnormal cells present which microscopy methods were not able to detect. Thus, complete remission is not synonymous with cure. People in complete remission can still relapse, and if they do, this is a bad prognostic sign. In this situation the prognosis is no better than if they had had no treatment. An alternate and more precise method to define complete remission is through examination of cell surface antigens.

Palliative treatment

It is important that patients don’t view this as a form of “non- treatment”. The aim of palliation is to optimise the individual’s quality of life in the remaining time that they have. Palliative care will often still involve chemotherapy and irradiation treatments, although the focus is provision of supportive care in the patient’s ideal environment.

Supportive care

This is the proper name given to the basic care given to both palliative and curative patients. It involves the following:

Reducing symptoms of anaemia – the patient will likely be subjected to frequent infusions of packed red cells, and, sometimes, irradiation of cells. Therapeutic measures should be aimed at maintaining leukemic patients on a Hb >10.

Prevention/control of bleeding – this is carried out by careful platelet count control. The count should be maintained at >10 in uninfected patients, and >20 in infected patients.

Treatment of infection – this involves two things: firstly, the education of the patient and the family about hand washing and isolation; secondly, the use of prophylactic antibiotics and anti-fungals.

Specific treatmentsAML

Curative treatment is attempted in almost all patients under 60. Those at low risk are given the initial remission induction which includes chemo + antibiotic, followed by four, 3-4 week cycles of remission consolidation. Those in high risk groups may only be given treatment if they have an HLA match for marrow transplantation.

Complete remission will be obtained in about ¾ of patients under 60. Failure may be due to a particularly invasive cancer, death from infection, or very rarely, death from bleeding. About 50% of those who achieve complete remission will be cured,i.e. in about 30% of patients the disease will never come back

If recurrence occurs, then prognosis is very poor. CR may be achieveable again, but this doesn’t carry with it a better prognosis.

Long survival is rarely achieved without transplantation

Acute promyelocyte leukaemia (APML)– this is an uncommon variant of AML, which involves a specific translocation mutation, t(15:17). There is almost always coagulopathy, and this is often the cause of death.

ATRA is a protein that causes differentiation of promyelocytes which can reduce the bleeding. Thus, the standard treatment for APML is now ATRA with chemotherapy to induce remission, followed by maintenance therapy with ATRA alone.

CR is obtained in about 80% of cases, and 60% of patients can expect to be cured.

The outlook is generally good compared to other types of AML, even after a relapse where remission may be achieveable again.

ALL – overall, the treatment is very similar to AML, but the drugs given may vary.

Again, transplantation is only recommended for those at high-risk, asin these cases ALL is considered generally incurable without transplantation.

Some patients will receive maintenance therapy for up to 2 years.

The major difference in treating AML and ALL is that ALL patients also get therapy directed at the CNS.

Approach to management of leukaemias

Prognosis

The prognosis for ALL in childhood is very good.

Complete remission is obtained in almost all patients.

80% will still be alive without recurrence after 5 years.

Failure of treatment occurs most commonly occurs in those with:

a high blast count

a T(9:22) translocation

The aforementioned factors related to failure increase in frequency with age.

The overall cure rate in children and adults is 70-80%. Failure to achieve remission with first- line therapies has a very poor prognosis. If second-line therapies achieve remission then they should be backed up with a positive HLA match for marrow transplant, i.e. usually that of a sibling, even though there is ahigh risk of graft versus host disease.

Most recurrences of the disease occur within 3 years, and recurrence is usually a very poor prognostic factor. CR can be obtained, but again are there likelihood of relapse.

Complications

Hyperviscosity syndrome results from increased circulating serum immunoglobulins in Waldenstrom macroglobulinaemia and multiple myeloma, but may also occur in hyperproliferative states such as the acute leukaemias, polycythemia and the myeloproliferative disorders in which there are increased cellular blood components. As serum proteins or cellular components rise, the blood becomes more viscous, leading to the following clinical symptoms:

Therapeutic leukapheresis is performed in patients with very high white blood cell counts, i.e. > 100,000 cells/mm3 and symptoms of leukostasis. Leukapheresis involves the removal of circulating blast cells followed by reinfusion of leukocyte-poor plasma. A single session can reduce the WCC by 20 to 50%.

Chronic Leukaemias

Chronic Myeloid Leukaemia

Almost exclusively an adult disease.

Accounts for 14% of all leukaemias.

The incidence is 2 per 100 000, being slightly higher in men.

Peak age of incidence is between 40-60 years.

Characterised by the presence of the Philadelphia (Ph) chromosome.

Whereas acute leukaemias are generally rapidly reversed or rapidly fatal, CML progresses slowly ; if CML is not treated, death will generally occur within 3-4 years.

Occurs mainly in later life, and increases in frequency with older age.

Results from a progressive accumulation of functionally incompetent B lymphocytes –hence the name!

Median survival is 10 years, and this is often related to the severity of symptoms at presentation.

Cytogenic and molecular abnormalities carry prognostic significance.

Clinical presentation

Many CML and CLL patients have no symptoms, but any of the following may be apparent: SOB due to anaemia, marrow failure and immunosuppression, splenic pain, weight loss, fever and sweats, lymphadenopathy, and hepatosplenomegaly.

CML usually presents in the chronic phase, whereas CLL is often asymptomatic and is discovered incidently.

Disease progression

Chronic phase – there may be an increased WCC; < 10% of blast cells in blood

Aggressive phase – more likely to find blast cells in the blood, i.e. approximately 10-20%, and more systemic symptoms

Blast phase – blood contains more than20% blast cells

Blast crisis

This is essentially the acute terminal phase of CML. Once patients reach this stage mortality is very high. The patient is said to be in a blast crisis, when there are more than 20-30% blast cells in the blood or bone marrow. Symptoms of a blast crisis include:

Investigations

Blood count –Hb low or normal; ↑ WBC; platelets low, normal or raised

Blood film –neutrophilia, i.e. abnormally high number of neutrophils, with myeloid precursors including blasts; in chronic leukaemia white blood cells are bigger, more mature and blast-like compared to the situation in other chronic disease

Cytogenetics – most common abnormality is deletion of 13q which translates into relatively benign disease status; trisomy 12 is present in 15% which is associated with progressive disease; mutation of IgVH on B cells is associated with poor prognosis, however IgVH is difficult to measure; intracellular ZAP-70, i.e. zeta-associated protein, correlates closely with IgVH mutated status and can be measured more easily in general laboratory

Coombs’ test – may be positive if there is haemolysis

Immunoglobulins – may be low or normal

Bone marrow aspiration

Bone marrow aspiration and biopsy with flow cytometry is not required in all cases of CLL, but may be necessary in some instances to establish a diagnosis and assess other complicating factors such as anaemia and thrombocytopaenia.

Management

Treatment depends on the stage of the disease, although cytogenetic markers are increasingly used. Clinical staging systems such as the Rai or Binet staging systems for CLL can help to determine when and how to treat the patient.

Chemotherapeutic intervention in early-stage disease is not usually necessary. The absolute indications for treatments are:

weight loss of more than 10% over 6 months

extreme fatigue

fever related to leukemia for longer than 2 weeks

night sweats for longer than 1 month

progressive marrow failure (anemia or thrombocytopenia)

autoimmune anemia or thrombocytopenia not responding to glucocorticoids

progressive or symptomatic splenomegaly

massive or symptomatic lymphadenopathy

progressive lymphocytosis, as defined by an increase of greater than 50% in 2 months or a doubling time of less than 6 months

According to NICE guidance, fludarabine monotherapy is not recommended for the first-line treatment of CLL.

Chlorambucil has been considered the drug of choice for first-line therapy of CLL, and when combined with prednisone, chlorambucil is associated with an initial response rate of 60-90% and a complete response in up to 20% of all patients.

Complications

Richter syndrome or transformation is seen in 3 to 10% of cases, where CLL is transformed into an aggressive, large B-cell lymphoma. Epstein-Barr virus may play a role in transformation. Lymph node biopsy is necessary for diagnosis. Patients will often present with:

weight loss

fever

night sweats

muscle wasting

increasing hepatosplenomegaly

lymphadenopathy

Pneumonia and/or septicaemia may occur due to the hypogammaglobinaemia and impaired T-cell function associated with CLL. Prophylactic antibiotics or immunoglobulin replacement therapy may be helpful.

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Dr Tom Leach MBChB DCH EMCert(ACEM) currently works as a GP Registrar and an Emergency Department CMO in Australia. He is also a Clinical Associate Lecturer at the Australian National University. After graduating from his medical degree at the University of Manchester in 2011, Tom completed his Foundation Training at Bolton Royal Hospital, before moving to Australia in 2013. He started almostadoctor whilst a third year medical student in 2009.
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